The use of organic nitrates in coronary diseases belongs today among the generally accepted therapeutic techniques. Originally it was observed that attacks of angina pectoris can be arrested by means of nitroglycerine and subsequently this therapy was extended to preventive treatment. Accordingly, a search has been undertaken for other substances having a similar effect but a longer duration of action. Among the large number of substances synthetized and tested from this point of view, isosorbide dinitrate (ISDN) has proved most acceptable. However, there continues to be a need for nitrates with a longer duration of action.
It has been recognized that the cause of the short half-life of ISDN is the rapid enzymatic biotransformation in the liver. During the metabolic process isosorbide 2-nitrate (2-ISM), isosorbide 5-nitrate (5-ISM), isosorbide (IS) and corresponding conjugates are mainly formed (S. F. Sisenwine and H. W. Ruelius, J. Pharmacol. Exp. Ther. 176:269, 1971).
R. L. Wendt, J. Pharmacol, Exp. Ther. 180:732, 1972 has demonstrated that 2-ISM and 5-ISM have the kind of action that is typical of nitrates. Further studies have show that these metabolites have substantial therapeutic advantages over the parent substance, particularly an improved absorption and thus a greater bioavailability, as well as a distinctly longer half-life. Thus the present use of sustained-action formulations needed to provide a prolonged effect may become superfluous. So far, however, the direct use of the mononitrates, particularly of 2-ISM, is hindered by the painstaking and very expensive synthesis of this compound.
According to I. G. Csizmadia and L. D. Hayward, Photochem. Photobiol. 4:657, 1965, 2-ISM is prepared by partial nitration of isosorbide. However the mixture resulting in this case contains 5-ISM, ISDN and IS with 2-ISM as a minor constituent only. Although 2-ISM can be obtained from this mixture by column chromatography, because of low yields and time-consuming and expensive mode of isolation, this method is of no practical importance.
Another method (M. Anteunis et al., Org. Magnet. Resonance 3:693, 1971) in which IS is converted first into ISDN and the latter is then partially hydrolyzed, also yields the aforementioned mixtures of ISDN, 2-ISM, 5-ISM and IS, whose separation and isolation cannot be carried out in an economically acceptable manner.
In German Offenlegungsschrift No. 2,751,934 and the corresponding U.S. Pat. No. 4,056,488 the following process is described: IS is acylated by means of an acid halide or anhydride, in the presence of an acid catalyst, to a mixture of IS, IS 2-acylate, IS 5-acylate and IS 2,5-diacylate. IS is extracted from this mixture, in order to prevent during the subsequent nitration step, the formation of ISDN which is known to present an explosion hazard. The remaining mixture of IS 2-acylate, IS 5-acylate and IS 2,5-diacylate is esterified with nitric acid, whereby a mixture of IS 2-acylate 5-nitrate, IS 5-acylate 2-nitrate and IS 2,5-diacylate is formed. From this, a mixture of 2-ISM, 5-ISM and IS is obtained by partial hydrolysis. The IS must again be removed by extraction, before the 2-ISM is isolated from the remaining residue by recrystallization from suitable solvents. Even by this method the desired 2-ISM is obtained only in a very moderate yield (24% of the theoretical).
All the aforementioned processes are characterized by the fact that no selective preparation of 2-ISM is possible; rather, mixtures are always obtained which must subsequently be separated into the individual constituents by appropriate separation methods. This mode of operation is painstaking and expensive. In each case it only allows the isolation of 2-ISM in low yields and hence does not permit a commercial preparation.
The first process for a selective preparation of 2-ISM was disclosed in German Offenlegungsschrift No. 2,903,983. In this process isomannide is converted by means of a halide or the anhydride of trifluoromethanesulfonic acid to isomannide 2-trifluoromethanesulfonate. The reaction of this product with an alkali metal nitrate, alkaline-earth nitrate or organic nitrate yields the desired end product under configuration reversal at the 2-carbon atom of the ring system.
Compared with the previously described methods, this process undoubtedly has the advantage of leading to a definite product in a clear sequence of only two reaction steps. However from the standpoint of economy it leaves much to be desired. Thus at the present time isomannide, used as starting product, is much more difficultly accessible and also considerably more expensive than isosorbide. The chemicals needed for the reaction are also decidedly expensive. Finally the overall yield which may be attained according to the indicated examples is only about 13% of the theoretical. Consequently this method likewise is not a suitable industrial process.
Hence there continues to be a need for processes for the preparation of 2-ISM which are based on readily accessible starting products and which provide the desired compound with the use of moderately priced chemicals, and in better yields than is possible according to the prior art.
The subject of the present invention is such an advantageous process for the preparation of isosorbide 2-nitrate.